Immune Tolerance in the GUT Relies on Dendritic Cells

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cover_natureThe differing origins of gut dendritic cells — white blood cells that modulate immune responses — may explain how the intestinal immune system manages to destroy harmful pathogens while tolerating beneficial bacteria says an article by Sophie Laffont & Fiona Powrie in Nature journal out on Dec 10th 2009.

The immune system must protect the body from invading pathogens without mounting damaging responses to its own tissues. Dendritic cells, a rare population of white blood cells, have a crucial role in determining the nature of immune reactions and in fine-tuning the balance between tolerance (where the immune system ignores or tolerates an antigen) and the induction of inflammation to destroy pathogenic organisms.Dendritic cells are important when considering the role of immunonutrition and the application of probiotics as therapy, as this family of cells has the discriminatory ability to define friend from foe and direct overall adaptive as well as innate immune responses.

Pioneering work by Steinman and colleagues in the early 1970s identified a minor population of immune cells that they named dendritic cells on the basis of their stellate shape and membranous processes. These cells were shown to be potent stimulators of another population of white blood cells, T cells.

Dendritic cells are strategically placed within mucosal sites in the body, where they can detect infection and take up microbial antigens. On activation, these cells migrate to secondary lymphoid tissue, such as the lymph nodes, where they present the antigen to T cells. This activates the T cells, causing them to differentiate into effector cells that eradicate the pathogen. In the intestine, dendritic cells also promote regulatory T-cell responses that suppress immune reactions against beneficial commensal bacteria and food antigens, thereby preventing immune-related disease. Thus, intestinal dendritic cells are decision makers, ensuring selection of a T-cell response that is appropriate to the nature of the challenge to the immune system.[1]


Keeping dendritic cells healthy and proportionate to response is one the mechanisms, favoured by the hygeine strategy to modulate local and systemic immune tolerance. The use of specific probiotics have demonstrated the ability to mature DC’s to promote the production of IL-10 and help maintain a position of immune unresponsiveness in the gastrointestinal and other tissues. These are sometimes called regulatory DC’s as they promote the creation of regulatory T cells and also assist in self tissue sampling reducing the risk of allergy and autoimmunity.[2],[3]


[1] Laffont S, Powrie F.Immunology: Dendritic-cell genealogy. Nature. 2009 Dec 10;462(7274):732-3. No abstract available. PMID: 20010677 [PubMed – in process] [2] Smits HH, Engering A, van der Kleij D, de Jong EC, Schipper K, van Capel TM, Zaat BA, Yazdanbakhsh M, Wierenga EA, van Kooyk Y, Kapsenberg ML.Selective probiotic bacteria induce IL-10-producing regulatory T cells in vitro by modulating dendritic cell function through dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin. J Allergy Clin Immunol. 2005 Jun;115(6):1260-7. View Abstract

[3] Latvala S, Pietila TE, Veckman V, Kekkonen RA, Tynkkynen S, Korpela R, Julkunen I. Potentially probiotic bacteria induce efficient maturation but differential cytokine production in human monocyte-derived dendritic cells. World J Gastroenterol. 2008 Sep 28;14(36):5570-83; View Full Article

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2 Comments. Leave new

  • I will be grateful for answers to the following questions:
    v.1) IS initiation is an important problem. Presently two theorems are proposed self-nonself and danger theory . Danger theory solves some problems in self-nonself theory e.g. lactation, pregnancy but is the correct theory one of them or a hybrid of them?

    v.2) If danger is the only mechanism for IS initiation then what is the difference between autoimmunity and hypersensitivity? After all both are pathogenic immune responses to ,normally, tolerated substances and cells.

    v.3) The rejection of the second pregnancy due to Rh differences between fetus and mother , one thinks, poses a serious problem to self-nonself theory. But why the second pregnancy and not the first one is rejected. An answer is proposed that the danger signals result from the first child “birth”. But one thinks that in this case the way of the birth (whether normal or cesarean) is expected to affect the duration of the second pregnancy before it fails (normal first birth gives a longer duration for the second pregnancy duration). Does this agree or disagree with observation?

    v.4) In anaphylaxes two mechanisms seem to be broken, the first is tolerance and the second is the control mechanism of the immune response. The immune response in the case of anaphylaxes may cause death!! The simultaneous breakdown of two mechanisms seems quite puzzling.
    Thank you for your help

    • Dear Ahmed

      Thank you for your questions, they are in need of greater depth of reponse than this service can provide, but the following may be helpful:
      v1. You have almost answered this question yourself, the danger theory expands on the self non self by allowing for recognition of non dangerous non self antigens and adds another level of subtelty to the evolving model. Where I feel the next stage of comprehension will be emerging is in the role of the actual involved tissues. Matzinger has already alluded to this in her own papers but other authors such as these are exploring this in greater detail. The interest from a clinical perspective is in the role of local tissue therapy as a component of immunological repair. The GI tract of course allows for the greatest level of tissue remodelling and chance for influence on immune status.
      v.2 Danger is of course a variable influence, in terms of the local tissues what is dangeous today may be tolerated tomorrow and vica versa.
      Normal tissue function and immune system homeostasis is maintained through balancing the need to activate an inflammatory immune response to eliminate invading pathogens with the need to minimise collateral damage to the tissue as a result of an over enthusiastic immune response. There are numerous mechanisms involving the tissue environment that help to avoid the generation of inflammatory T cells and prevent those that are generated from causing tissue damage. One of the key checks takes place during T cell priming in lymphoid organs and determines whether a T cell becomes activated or deleted and, if activated, what type of effector or regulatory functions it will gain.

      Dendritic cells (DCs) are central to this decision-making process and their regulatory properties are influenced by the signals they receive from the tissue environment. This has been well established for intestinal DCs, which gain immune regulatory properties from the gut environment and imprint gut-homing specificity on T cells.

      DC’s in the gut will sample exogenous and endogenous antigens to impart immune tolerance, a change in the DC subsets, or their environment can lead to altered response to both sets of antigen, which may as in the case of coeliac lead to a condition that may then be described as an organ specific auoimmune disease. Autoimmuity and hypersensitivity are therefore best viewed as places along an immunological continuem, in which there are many shared components, with differing levels of intensity, promoted by environmental influences and embedded in genetic inheritance.

      v3 I have no substantive comment, but find your thinking and questioning very interesting.

      v4. Anaphylaxis remains a rare and as you state life threatening condition. The simulatanous overwhelming response resulting from the immunologically induced release of mast cell and/or basophil mediators after exposure to a specific antigen in previously sensitised individuals can have immediate and delayed adverse effects on human health. Histamine remains a complex molecule and whilst is is argued that histamine is not realy an imune response, it obviously has powerful immune outcomes. You are correct that this remains a puzzling dilemma for which, whilst uncommon appears to be increasing and for which only reactive treatment has shown reliable interventions. The hygeine – modified theory has many possible explanations and Kings College in London is exploring peanut exposure that may provide some clarification on risks, mechanisms and prevention.


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